tbuckley/cabot-search huggingface dataset:
Abstract 6092: The dual roles of C-X-C MOTIF chemokine LIGAND 10 in pediatric osteosarcoma
Authors: Xiang Chen, Margaret Clement, John Hicks, Tsz Kwong Man
Journal: Cancer Research (2022)

Abstract Osteosarcoma is the most common malignant bone tumor in children and young adults. Despite the use of multi-agents chemotherapy and aggressive surgery, the survival of patients with osteosarcoma remains at 60% over the past three decades. In addition, the survival of patients who develop metastasis is dismal and often less than 25%. We have previously reported that serum C-X-C motif chemokine ligand 10 (CXCL10) is associated with survival in a large cohort of osteosarcoma patients. CXCL10 is an interferon-induced chemokine that binds to its cognate receptor CXCR3 to elicit its cellular effects via both autocrine and paracrine signaling. CXCL10 can promote tumor cell migration and metastasis via autocrine signaling, while it recruits CXCR3+ immune cells to exert a tumoricidal effect via paracrine signaling. However, little is known about the effect of circulating CXCL10 in cancer. To understand the role of CXCL10 in the pediatric bone tumor, we showed that a number of osteosarcoma cell lines expressed the CXCR3 protein. The addition of exogenous CXCL10 promoted tumor cell migration of three osteosarcoma cell lines but did not affect cell proliferation. However, the migratory effect of osteosarcoma cells is not specific to CXCL10, as other CXCR3-associated chemokines (CXCL4, CXCL9, and CXCL10) exerted similar effects. Using an orthotopic xenograft mouse model, we demonstrated intravenous injection of CXCL10 increased the development of pulmonary metastases of osteosarcoma. In contrast, expression profiling of osteosarcoma primary tumors showed that elevated expression of CXCL10 and CXCR3 was associated with a better prognosis, suggesting that a paracrine effect of CXCL10 by recruiting CXCR3+ immune cells to the tumor site. This notion is supported by our immune cell population deconvolution results, indicating that the predominant infiltrating immune cell types are macrophages and CD8+ T cells. Taken together, our results suggest a model in which CXCL10 may play both pro-tumor and anti-tumor roles in osteosarcoma. While a high level of exogenous or circulating CXCL10 may promote tumor cell migration and metastasis, the chemokine can also recruit CXCR3+ immune cells to exert a favorable prognostic effect. Further characterization of the sources of CXCL10 in the tumor site and circulation may lead to the development of a therapeutic approach that promotes CXCL10’s anti-tumor effects and minimizes its pro-tumor effects to improve the survival of osteosarcoma patients. Citation Format: Xiang Chen, Margaret Clement, John Hicks, Tsz Kwong Man. The dual roles of C-X-C MOTIF chemokine LIGAND 10 in pediatric osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6092.
Abstract 5225: The PI3K inhibitor Paxalisib combines with the novel HDAC1/3 inhibitor RG2833 to improve survival in mice bearing orthotopic xenografts of atypical teratoid/rhabdoid tumors
Authors: Tyler Findlay, Kristen Malebranche, Charles Eberhart, Eric Raabe, Jeffrey Rubens
Journal: Cancer Research (2022)

Abstract Atypical teratoid/rhabdoid tumors (AT/RT) are the most common malignant brain tumors of infancy with a four-year event-free survival of 37%. Previously, we have identified high activation of both mTORC1 and mTORC2 through immunohistochemistry of 18 primary human AT/RT. The PI3K-Akt-mTOR signaling pathway drives tumorigenicity by promoting cancer cell growth and survival. Paxalisib is a highly brain-penetrant PI3K inhibitor acting upstream of mTORC1/2 to fully inhibit the activation of both complexes. Ongoing pediatric clinical trials have reported Paxalisib as safe and well-tolerated, with minimal dose limiting toxicities. Paxalisib treatment in mice bearing orthotopic xenografts of AT/RT slowed tumor growth and significantly extended survival from 40 to 54 days (bioluminescent imaging, log rank test p=0.0011). However, due to limited durability of single agent therapy, we conducted pilot studies to identify rational combination therapies to enhance Paxalisib survival benefits in AT/RT. RG2833 is a novel, highly brain penetrant, histone deacetylase 1/3 (HDAC1/3) inhibitor. Our preliminary data has shown that Paxalisib and RG2833 combine synergistically to decrease AT/RT cell growth (SynergyFinder ZIP score 11.1; CellTiter-Blue Cell Viability Assay, p&amp;lt;0.0001), and increase apoptosis (Western blot cPARP, MUSE Annexin V Assay, ANOVA p&amp;lt;0.001) compared to each agent alone and DMSO control. Additionally, our pilot combination study in orthotopic xenograft models of AT/RT demonstrated that combination therapy slows tumor growth more significantly than each agent alone and vehicle control (bioluminescent imaging). This novel combination therapy will readily translate into a new clinical trial aimed at improving survival in this deadly pediatric brain tumor. Citation Format: Tyler Findlay, Kristen Malebranche, Charles Eberhart, Eric Raabe, Jeffrey Rubens. The PI3K inhibitor Paxalisib combines with the novel HDAC1/3 inhibitor RG2833 to improve survival in mice bearing orthotopic xenografts of atypical teratoid/rhabdoid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5225.
Investigational PET tracers in neuro-oncology—What’s on the horizon? A report of the PET/RANO group
Authors: Norbert Galldiks, Karl-Josef Langen, Nathalie L Albert, Ian Law, Michelle M Kim, Javier E Villanueva-Meyer, Riccardo Soffietti, Patrick Y Wen, Michael Weller, Joerg C Tonn
Journal: Neuro-Oncology (2022)

Many studies in patients with brain tumors evaluating innovative PET tracers have been published in recent years, and the initial results are promising. Here, the Response Assessment in Neuro-Oncology (RANO) PET working group provides an overview of the literature on novel investigational PET tracers for brain tumor patients. Furthermore, newer indications of more established PET tracers for the evaluation of glucose metabolism, amino acid transport, hypoxia, cell proliferation, and others are also discussed. Based on the preliminary findings, these novel investigational PET tracers should be further evaluated considering their promising potential. In particular, novel PET probes for imaging of translocator protein and somatostatin receptor overexpression as well as for immune system reactions appear to be of additional clinical value for tumor delineation and therapy monitoring. Progress in developing these radiotracers may contribute to improving brain tumor diagnostics and advancing clinical translational research.
Abstract 1201: GenomeCruzer: A tool for interactive 3D visualization and analysis of multidimensional cancer omics
Authors: Claudio Isella, Riccardo Corsi, Jamal Elhasnaoui, Andrea Bertotti, Luca Vezzadini, Enzo Medico
Journal: Cancer Research (2022)

Abstract In cancer genomics, integrative analysis of data obtained from biological samples of patient cohorts requires handling large groups of patients, each with molecular data of different type for thousands of genes, such as expression, mutation, copy number, and others. Currently available tools allow visualization and analysis of such complex data, however forcing the user to work with partial views due to the amount of information. Also, these systems usually involve somewhat laborious procedures, so that for a complete analysis of the information it is often necessary to use many tools in sequence. Here we present GenomeCruzer, a software for 3D interactive visualization and analysis of multidimensional omic data sets (e.g. gene expression, methylation, copy number alteration). GenomeCruzer is particularly useful to quickly achieve clinical and biological insight, providing easy integration and interactive visualization of genomic data of any kind. GenomeCruzer has the dual objectives of representing large amounts of genomic data in an easily readable way, allowing interactive analysis and providing visual results in real-time. Powerful graphics also allow simultaneous display of different types of values for the same objects, through multiple dimensions and customizable visual metaphors. The user can navigate this 3D environment and interact with the different elements, which constitute a representation of the starting datasets, building analysis paths and using statistical tools e.g. for the comparison of groups to highlight correlations. In conclusion, GenomeCruzer enables users without bioinformatics background to browse, analyse and interpret complex omics datasets for multiple groups of patients and genes simultaneously, extracting clinical correlates and biological knowledge. Citation Format: Claudio Isella, Riccardo Corsi, Jamal Elhasnaoui, Andrea Bertotti, Luca Vezzadini, Enzo Medico. GenomeCruzer: A tool for interactive 3D visualization and analysis of multidimensional cancer omics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1201.
Abstract 1539: LKB1 down-modulation by miR-17 biologically and clinically mirrors LKB1-mutated NSCLC
Authors: Cristina Borzi, Monica Ganzinelli, Elisa Caiola, Marika Colombo, Giovanni Centonze, Mattia Boeri, Laura Caleca, Ugo Pastorino, Mirko Marabese, Massimo Milione, Massimo Broggini, Marina C. Garassino, Gabriella Sozzi, Massimo Moro
Journal: Cancer Research (2022)

Abstract Introduction: In non-small cell lung cancer (NSCLC) LKB1 mutations combined with KRAS hyperactivation define a poor responsive, aggressive and disseminating phenotype. We recently unveiled the vulnerability of KRAS/LKB1 co-mutated (KL) patient-derived xenografts (PDXs) to metabolic stress-based treatments, and a clinical trial to test the efficacy of metformin and fasting-mimicking diet on KL NSCLC is currently ongoing in our Institute. Besides inactivating mutations, LKB1 functionality may be impaired by post-translation regulation. Because miR-17 is a potential epigenetic regulator of LKB1,we hypothesized that wild-type LKB1 (LKB1WT) NSCLC with high miR-17 expression may biologically and clinically mirror LKB1 mutated tumors. Methods: NSCLC cell lines with different combinations of KRAS mutation and LKB1 deletion were selected, together with a panel of PDXs with high (LKB1WT/miR-17 high) or low (LKB1WT/miR-17 low) miR-17 expression. Taking advantage of series of NSCLC patients and PDXs, we retrospectively evaluated LKB1 and miR-17 expression levels in tumor tissue specimens. In addition, the TCGA dataset was interrogated for miR-17 expression and potential correlation with lung cancer clinical features. Results: Direct targeting of miR-17 to LKB1 3’UTR was confirmed by luciferase reporter assay. We found that miR-17 overexpression in LKB1WT cell lines functionally impaired the LKB1/AMPK pathway, and prompted apoptotic response to metformin. Of note, LKB1WT/miR-17 high PDXs tumor cells showed a similar behavior upon metformin treatment. A retrospective analysis in patients with NSCLC revealed an inverse correlation between miR-17 and LKB1 expression, and highlighted a prognostic role of miR-17 expression in LKB1WT patients, further confirmed by TCGA data analysis. Conclusions: We validated miR-17 as epigenetic regulator of LKB1 expression in NSCLC tumors. We propose a miR-17 expression score potentially exploitable to discriminate LKB1WT NSCLC patients with impaired LKB1 expression and poor outcome, eligible for energy-stress-based treatments. Citation Format: Cristina Borzi, Monica Ganzinelli, Elisa Caiola, Marika Colombo, Giovanni Centonze, Mattia Boeri, Laura Caleca, Ugo Pastorino, Mirko Marabese, Massimo Milione, Massimo Broggini, Marina C. Garassino, Gabriella Sozzi, Massimo Moro. LKB1 down-modulation by miR-17 biologically and clinically mirrors LKB1-mutated NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1539.
Abstract 5925: Albumin-bilirubin score as a marker for predicting occurrence of hepatocellular carcinoma in patients with liver cirrhosis
Authors: Nobuyuki Toshikuni, Mutsumi Tsuchishima, Mikihiro Tsutsumi, Joseph George
Journal: Cancer Research (2022)

Abstract Background: The newly developed albumin-bilirubin (ALBI) score has been proved to be a simple and useful marker for predicting prognosis in patients with hepatocellular carcinoma (HCC). However, evidence is scarce regarding the use of ALBI score to predict occurrence of HCC in patients with chronic liver disease. In the current study, we examined the usefulness of ALBI score to predict occurrence of HCC in patients with liver cirrhosis. Methods: In this retrospective study, we included only cirrhotic patients without previous history of HCC. A total of 68 cirrhotic patients (median age, 68 years old; 36 males and 32 females; 42 compensated and 26 decompensated cirrhosis) were included. Using a Cox proportional hazard model, we identified the risk factors for HCC occurrence and mortality. The potential factors were age, gender, causes of cirrhosis (hepatitis virus infection vs others), platelet count, serum alpha-fetoprotein (AFP) level, serum endocan level, ALBI score, and successful treatment for cirrhosis (yes vs no). Results: The leading cause of cirrhosis was hepatitis virus infection (9 HBV- and 20 HCV-infected patients), followed by alcohol-related liver disease (23 patients), nonalcoholic steatohepatitis (5 patients), and other causes (2 patients). The median follow-up period was 10 years. During the study period, 16 patients had HCC and 22 patients died (12 liver failure, 3 HCC, 2 variceal rupture, 2 bacterial infection, and 3 other causes). Cumulative survival rates were 92%, 72%, and 59%, at 5, 10, and 15 years, respectively. Regarding risk factors for HCC occurrence, univariate analysis identified a low platelet count and an increased ALBI score as significant factors. However, on multivariate analysis, an increased ALBI score was the only significant factor [hazard ratio, 7.49 (1.65−34.04); p = 0.009]. Regarding risk factors for mortality, univariate analysis identified older age as the only significant factor; male gender and hepatitis virus infection tended to be significant. However, on multivariate analysis, older age, male gender, and hepatitis virus infection were significant factors. Conclusion: The results indicate that an increased ALBI score is a useful factor to predict occurrence of HCC in patients with liver cirrhosis. Citation Format: Nobuyuki Toshikuni, Mutsumi Tsuchishima, Mikihiro Tsutsumi, Joseph George. Albumin-bilirubin score as a marker for predicting occurrence of hepatocellular carcinoma in patients with liver cirrhosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5925.
Abstract 3350: TSEEN genes database
Authors: Ekaterina Matyunina, Andrei Makashov, Andrei P. Kozlov
Journal: Cancer Research (2022)

Abstract According to the hypothesis of the evolutionary role of tumors, evolutionarily new genes should be specifically expressed in tumors [A.P. Kozlov, 2014]. Indeed, TSEEN (tumor specific evolutionarily novel) genes were described by us [Kozlov, 2016]. 1015 genes were identified by the Protein Historian program as evolutionary novel for humans, that is, originated in humans, and 1392 as evolutionarily young, that is, originated in primates. As a result of analyzing the GTEx database data, we have shown that out of 1015 evolutionarily new human genes and 1392 evolutionarily young human genes, 309 genes and 592 genes are not expressed in any of 33 normal tissues, respectively. The expression level of 101 evolutionarily new human genes originated in humans and 233 evolutionarily young human genes originated in primates is significant in most tumors, according to transcriptome data from the TCGA database. Samples of 101 evolutionarily novel human genes and 233 evolutionarily young human genes were selected, which are present only in the genomes of humans and primates, not expressed in normal tissues, and expressed in one or more tumors in 10-100% of patients.For Theria and Eutheria, the similar distribution was as follows: among 365 and 896 genes novel for these taxons, 71 and 124 genes, respectively, are not expressed in normal human tissues, respectively, but at the same time have tumor-specific expression pattern (inclusion criteria of expression - fpkm &amp;gt;2 in 10-100% of patients).There are also 898 genes, originated in mammalia and not expressed in normal human tissues. 119 of them are expressed in at least 1 or more tumors in 10-100% of patients.The TSEEN genes database allows [us] to select genes according to their evolutionary age and expression pattern in normal and tumor tissues. We can retrieve gene(s), which are expressed tumor-specifically and are evolutionarily young or novel.As far as TSEEN genes have many immunogenic epitopes they could be promising targets for development of universal prophylactic and therapeutic antitumor vaccines, as well as universal markers for cancer laboratory diagnostics.Created TSEEN genes database is available at: https://tseendb.org/#/ Citation Format: Ekaterina Matyunina, Andrei Makashov, Andrei P. Kozlov. TSEEN genes database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3350.
Diabetes Distress, Depressive Symptoms, and Anxiety Symptoms in People With Type 2 Diabetes: A Network Analysis Approach to Understanding Comorbidity
Authors: Amy M. McInerney, Nanna Lindekilde, Arie Nouwen, Norbert Schmitz, Sonya S. Deschênes
Journal: Diabetes Care (2022)

OBJECTIVE In this study, we aimed to explore interactions between individual items that assess diabetes distress, depressive symptoms, and anxiety symptoms in a cohort of adults with type 2 diabetes using network analysis. RESEARCH DESIGN AND METHODS Participants (N = 1,796) were from the Montreal Evaluation of Diabetes Treatment (EDIT) study from Quebec, Canada. A network of diabetes distress was estimated using the 17 items of the Diabetes Distress Scale (DDS-17). A second network was estimated using the DDS-17 items, the nine items of the Patient Health Questionnaire (PHQ-9), and the seven items of the Generalized Anxiety Disorder Assessment (GAD-7). Network analysis was used to identify central items, clusters of items, and items that may act as bridges between diabetes distress, depressive symptoms, and anxiety symptoms. RESULTS Regimen-related and physician-related problems were among the most central (highly connected) and influential (most positive connections) in the diabetes distress network. The depressive symptom of failure was found to be a potential bridge between depression and diabetes distress, being highly connected to diabetes distress items. The anxiety symptoms of worrying too much, uncontrollable worry, and trouble relaxing were identified as bridges linking both anxiety and depressive items and anxiety and diabetes distress items, respectively. CONCLUSIONS Regimen-related and physician-related diabetes-specific problems may be important in contributing to the development and maintenance of diabetes distress. Feelings of failure and worry are potentially strong candidates for explaining comorbidity. These individual diabetes-specific problems and mental health symptoms could hold promise for targeted interventions for people with type 2 diabetes.
Abstract 3611: Determining the regulation and role of mreg DC in tumor immunity
Authors: Raphael Mattiuz, Nima Assad, Pauline Hamon, Assaf Magen, Jessica Le Berichel, Miriam Merad
Journal: Cancer Research (2022)

Abstract Therapeutic immunity against tumors is mainly determined by effector T cells. However, T cells are educated by antigen presenting cells, particularly dendritic cells (DC), that control their differentiation into effector T cells able to eliminate target tumor cells. While most studies focused on understanding T cell features leading to antitumor immunity, little is known about DC determinants required to promote effective antitumor T cell function. Yet several studies are revealing that high DC content in tumor lesions correlate with improved tumor outcome. To identify molecular program that modulate DC functionality in tissues we have profiled tumor-associated DC in mice and tumor lesions. We identified a DC molecular program that was shared between mice and human tumors that included maturation genes associated with T cell simulation and migration to the LN (Cd40, Cd80, Fscn, Ccr7), but also genes associated with immunoregulation (Socs1, Socs2, Socs3, Cd200, Pd-l1, Pd-l2, Fasl), we named mregDC (Maier et al., Nature 2020). We also found that mregDC molecular state is induced in DC1 and DC2 upon capture of tumor debris leading to hypothesize that the mregDC state identifies antigen-charged DC that migrate to lymphoid structures, including tertiary lymphoid structures and tumor draining lymph nodes to modulate tumor specific T cell immune responses. While the role of DC in the draining LN has been established the exact role played by DC in the tumor microenvironment (TME) remains unclear. To explore this question, we used multiplex imaging and spatial transcriptomics platforms to identify the distribution and spatial interactions of DC1, DC2 and mregDC within the TME of human NSCLC and HCC lesions during treatment with PD-1 blockade. We found that mregDC accumulate within the tertiary lymphoid structures together with activated T cell and B cell programs. We are continuing to generate additional data on mregDC interactions in human tumors tissues that respond or resist PD-1 blockade and should be able to provide additional information at the time of the meeting. Citation Format: Raphael Mattiuz, Nima Assad, Pauline Hamon, Assaf Magen, Jessica Le Berichel, Miriam Merad. Determining the regulation and role of mreg DC in tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3611.